Efficacy and Safety of Sacubitril/Valsartan Versus Amlodipine in Japanese Patients With Essential Hypertension: A Randomized, Multicenter, Open-Label, Noninferiority Study (PARASOL Study)

Abstract

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has demonstrated a superior blood pressure-lowering effect compared with renin-angiotensin system inhibitors in several clinical trials. However, there has been no available evidence on the comparison between sacubitril/valsartan and calcium channel blockers (CCBs), a well-established class of antihypertensive drugs. In this open-label, multicenter study, we aimed to demonstrate the efficacy and safety of sacubitril/valsartan versus amlodipine, one of the most widely used CCBs, after 8 weeks of treatment. A total of 359 Japanese patients with essential hypertension (office systolic blood pressure [SBP] ≥ 150 to < 180 mmHg), aged 18-79, were randomly assigned to receive either once-daily sacubitril/valsartan 200 mg or once-daily amlodipine 5 mg in a 1:1 allocation ratio. The primary endpoint was the noninferiority of sacubitril/valsartan compared with amlodipine in mean change in 24-h SBP from baseline to Week 8, followed by a significance test as a secondary endpoint analysis. The mean change in 24-h SBP in sacubitril/valsartan was noninferior to that in amlodipine (between-treatment difference -0.62 mmHg [95% confidential interval: -3.23 to 1.98; p = 0.003 for noninferiority; independent t-test with noninferiority margin 3.0 mmHg]), with no significant difference observed (p = 0.637). There was no significant difference in the incidence of adverse events (AEs). These results suggested that the blood pressure-lowering effect of sacubitril/valsartan is comparable to that of amlodipine, with no marked differences in tolerability between the two groups. Sacubitril/valsartan, a potent antihypertensive drug comparable to amlodipine, is expected to improve blood pressure control in clinical practice.

Keywords: ambulatory blood pressure monitoring; angiotensin receptor‐neprilysin inhibitor; calcium channel blocker; essential hypertension; sacubitril/valsartan.

FIGURE 1

Changes in 24‐h SBP (A) and DBP (B) from baseline to Week 8, and hourly average ambulatory SBP (C) and DBP (D) at baseline and Week 8. Error bars represent standard error. DBP indicates diastolic blood pressure; SBP, systolic blood pressure.

FIGURE 2

Proportion of patients who achieved ambulatory or office BP control and response rate at Week 8. (A) BP control was defined as follows. Ambulatory BP control: 24‐h SBP/24‐h DBP < 130/80 mmHg for patients < 75 years of age, and < 140/90 mmHg for ≥ 75 years of age. Office BP control: SBP/DBP < 130/80 mmHg for patients < 75 years of age, and < 140/90 mmHg for ≥ 75 years of age. (B) SBP response rate was defined as follows. Ambulatory SBP: 24‐h SBP < 130 mmHg at Week 8 for patients < 75 years of age, as 24‐h SBP < 140 mmHg for ≥ 75 years of age, or a reduction ≥ 20 mmHg from baseline. Office SBP:  SBP < 130 mmHg at Week 8 for patients < 75 years of age, as < 140 mmHg for ≥ 75 years of age, or a reduction ≥ 20 mmHg from baseline. (C) DBP response rate was defined as follows. Ambulatory DBP: 24‐h DBP < 80 mmHg at Week 8 for patients < 75 years of age, as 24‐h DBP < 90 mmHg for ≥ 75 years of age, or a reduction ≥ 10 mmHg from baseline. Office DBP:  SBP/DBP < 80 mmHg at Week 8 for patients < 75 years of age, as < 90 mmHg for ≥ 75 years of age, or a reduction ≥ 10 mmHg from baseline. p values obtained from Fisher's exact test. ABPM indicates ambulatory blood pressure monitoring; BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure.

FIGURE 3

Waterfall plot of individual (A) 24‐h SBP and (B) 24‐h DBP changes from baseline to Week 8. DBP indicates diastolic blood pressure; SBP, systolic blood pressure.